|+ glucose t
urea); normal £10 mmol/L
abnormal osmolar gap indicates the presence of alcohols
5.If anion gap is increased, is the change in bicarbonate the same as the change in anion gap?
if not, consider a mixed metabolic picture
Acidosis «»Hyperkalemia
Alkalosis••Hypokalemia
Note: Mixed acid-base disturbances can
Table 9. Differential Diagnosis of Respiratory Acidosis still have a "normal" pH
Incieosed MOisecondory tohypovonIdalion
Neuromuscular Disorders
(Decreased Vital Capacity)
Myasthenia gravis
Guillain -Barre syndrome
Botulism
Poliomyelitis
Muscular dystrophies
Mechanical Hypoventilation
(Inadequate Mechanical
Ventilation)
Respiratory Centre Depression
(Decreased RR)
Drugs (anesthesia,sedatives,
narcotics)
Iraume
Encephalitis
Stroke
Central apnea
Supplemental Ol in chronic C02
retainers (e.g. C0P0)
Lung Disease
Chronic:C0P0.CF
Acute: Asthma
Pulmonary edema
Pneumothorax
Pneumonia
ri
L J
Osmolar Gap - measured osmolarity
- calculated osmolarity:for calculated
osmolarity think "2 salts and a sticky
BUN”(2Na +glucose + urea)
ILD (late stage)
ALS -IT'
*
Myopathies +
Chest wall disease (obesity,
kyphoscoliosis)
R6 Respirology Toronto Notes 2023
Table 10. Differential Diagnosis of Respiratory Alkalosis
Oectcan'd P<iCO:se<ondoty to hypeivtnlilotion
Anion Gap Metabolic Acidosis
Systemic Diseases
Pulmonary disease (pneumonia,edema.PE.
interstitial fibrosis)
Severe anemia
Heart failure
Respiratory Centre Stimulation
Drugs (ASA.progesterone,theophylline,
catecholamines,psychotropics,nicotine,
salicylates)
Hepatic failure
Gram-negative sepsis
Pregnancy
Anxiety
Mechanical Hyperventilation
(Excessive Mechanical Ventilation) MUDPILESCAT
Methanol
Uremia
Diabetic ketoacidosis/starvation
ketoacidosis
Phenformin/Paraldehyde
Isoniazid.Iron.Ibuprofen
Lactic acidosis
Ethylene glycol
Salicylates
Cyanide.Carbon dioxide
Alcoholic ketoacidosis
Toluene. Theophylline
Pain
High altitude
• see Nephrology. N PIS for differential diagnosis of metabolic acidosis and alkalosis
What is the P.Or? (normal 95-100 mntHy)
I
fP,0;<95 mmHg j
*
At Sea Level on Room Air
FiOr‘0.21
Hlem - 760 mmHg
PHrO - 47 mmHg
RO -0.8
Thus.A-aDCC gradient on room air
A-aDQ -(150 -1.25[PaOrfl- PaOr
P1O2
-(FiOz x (barometric pressure -
PHrO))
What is the A-a gradient?
(normal <15 mmHg but increases with age)
I
T r
Increased A-a gradient (>15 mmHg)=lung disease [ Lung normal A-a gradient|<15 mmHgl = normal lungs ]
• Decreased DLco
T T
i
Increased ft C0r
• Hypoventilation
Normal P.CQ
• Low PiQ
(e.g.high altitude)
( Give 100% 0,
£ jr_ Diffusion Capacity for CO
PjOrimproves
• V/Q mismatch
• Airway disease (asthma. C0PD)
• ILD
• Alveolar disease
• Pulmonary vascular disease
P.Qdoes not improve
• Shunt
• Anatomical (intracardiac or
intrapulmonary)
• Physiological (severely
consolidated or atelectatic
lung)
DLco decreases in:
. ILD
• Pulmonary vascular disease
• Anemia
. Emphysema (decreased surface area)
DLco increases in/with:
• Asthma
• Obesity
• Pulmonary hemorrhage
• L eft to right intracardiac shunt
• Polycythemia
• Post exercise physiology (increased
pulmonary blood volume)
Figure 7. Approach to hypoxemia
0r= 150 mmHg
C0r= 0
B
Or- 40
CO- 45
Pulmonary Shunt
When blood bypasses the alveolar
membrane by means of an abnormal
circulation pathway and reaches the
pulmonary venous system with deoxygenated hemoglobin.
Shunt like physiology occurs when
blood passes through areas of the lung
that have very little ventilation (e.g.
densely consolidated lung in a severe
pneumonia).
Shunt :Q- 45 Dead Space
O; -4
Normal
* 00
Decreasing
Vx /Q
Increasing
V*
/Q
Figure 8. Pathophysiology of V/Q mismatch
Flguie adapted from West- Respiratory Physiology: The Essentials.9thEd. 2012. lippincott Williams & Wilkins.Philadelphia, PA.
1
+
R7 Respirology Toronto Notes 2023
Airway Disease
Pneumonia Airway Obstruction (Decreased FEVi)
. Asthma
• COPD (chronic bronchitis,
emphysema)
• Bronchiectasis (obstructive or mixed)
• Cystic fibrosis (obstructive or mixed)
• see Paediatrics, P93
Asthma
<§>
•see Family Medicine. 1M19 and Paediatrics, P9I
Definition
•chronic inflammatory disorder of the airways resulting in episodes of reversible bronchospasm
causing airflow obstruction
•associated with reversible airflow limitation and airway hvper-responsiveness to endogenous or
exogenousstimuli
•inflamed airways undergo a variety of changes including hypertrophy of airway smooth muscle and
hyperplasia of mucous producing goblet cells
Epidemiology
•common, 10.8% of Canadians (3.8 million);8-10% of adults, 10-15% of children (however often
“overdiagnosed” because inaccurate clinical diagnosis, failure to use objective testing)
•most children with asthma significantly improve in adolescence
•often family history of atopy (asthma, allergic rhinitis, eczema )
•work-related asthma (includes work-exacerbated asthma or occupational asthma caused hy high or
low molecular weight sensitizer exposure)
Red Flags
Severe tachypnea/tachycardia,
respiratory muscle fatigue, diminished
expiratory effort cyanosis,silent chest,
decreased IOC
Central cyanosis is not detectable until
SaOjis <85%. It is more easily detected
in polycythemia and less readily
detectable in anemia
Pathophysiology
Severe asthma attack:
•airway obstruction * V/Q mismatch >
•hypoxemia * t ventilation •»
*
PaCiO > » tpH and muscle
fatigue * *ventilation, t PaQ)
’
/
*
pH
Signs and Symptoms
•dyspnea, wheezing, chest tightness, cough,sputum
•symptoms usually occur or worsen at night or early morning
•symptoms can be paroxysmal or persistent
•when having an asthma attack: signs of respiratory distress, pulsus paradoxus
Asthma Triggers
Irritants,such as:
. URTIs
• Emotion/anxiety
t Cold air
• Exercise
. GERD
• Cigarette smoke, air pollution
• Strong scents
Allergens,such as:
• Pet dander
• House dust
• Mould Table 11 « Cockroaches . Criteria for Determining if Asthma is Well Controlled
• Seasonal allergens (grassj'tree/weed/
ragweed)
Daytime symptoms <2 d/wk
Night-time symptoms <1 night/wk
Physical activity normal (unimpaired by symptoms)
Exacerbations mild, infrequent (no ER visit, hospitalization, use oi
prednisone)
No asthma -related absence from work/school
p2- agonist use <2 times/wk
FEVi or PEf >M% of personal best
PEE diurnal variation <10-15%
Other:
• NSAIDs (Samter'
s triad ^ asthma.
NSAID sensitivity, nasal polyps)
• |3 blockers (especially noncardioselective)
Can JRcspli Crll Cnru Sleep Med 2021: 5:0.348- 351 • Hormonal fluctuations
Table 12. Pulmonary Function Criteria for Diagnosis of Asthma (in ages 6+)
Preferred Measurement Alternative Measurements
Signs of Poor Asthma Control Spirometry Showing Reversible Airway Obstruction
1. 4 FEVt/FVC below lower limit of normal
Adults:typically <0.75 to 0.8
Children age 6>: typically < 0.8 0 9
Peak Expiratory Flow Variability
1.1 in PEE after a bronchodilator or couisc of controller therapy
Adults: PEF increase > 60 L /min (and >20%) OR
Diurnal variation >8% loi twice daily readings|
- 20% lor multiple
daily readings)
Children age 6*: PEF increase >20%
•DANGERS"
Daytime Sx >3d/wk
Activities ( physical) reduced
Night-time Sx >1 night/wk
GP visits (unscheduled visits for
exacerbations,requiring steroids)
ER visits or hospitalizationsfor
exacerbations
Rescue puffer (SABA) use >3times/wk
School or work absences
AND
2. t FEVt >12% (and >200 ml in adults) after bronchodilator or a
course of controller therapy
PositiveChallenge Test
1. Methacholine challenge: positive if FEV r 4 >20% at anyinhaled
methacholine dose <4 mg/ml (borderline if 4-16 mg/ml is required)
2. Post-exercise: 4 FEVi >1015%
Adapted horn: Can J Respir Cut Care Sleep Med 2021:5:6.348-351
Treatment
• environment: identify and avoid triggers
• patient education:features of the disease,goals of treatment,self-management asthma action plan,
inhaler technique
• pharmacological
• symptomatic relief in acute episodes:short
-acting (12-agonist or combined, long acting (12-agonist
with inhaled corticosteroid (formoterol/budesonide)
r -\
L J
+
R8 Rcspirology Toronto Notes 2023
• long-term maintenance: any patient with poor control ( Table 11, 1(7) and/or at risk of
exacerbationsshould be on an inhaled corticosteroid-containing regimen (see l igure 9)
risk of exacerbation defined as any of:1) history of a previous requiring any of:systemic steroids,
ED visit or hospitalization, 2) poorly-controlled asthma, 3) overuse of SABA (defined as use of
more than 2 inhalers of SABA in I year), or 4) current smoker
1. start with daily inhaled corticosteroids(or long acting p2-agonist with inhaled
corticosteroid (formoterol/budesonide) as needed in patients 12 y/o - especially in
patients expected to have low adherence to a daily inhaled corticosteroid)
2. add long-acting p2-agonists to low dose inhaled corticosteroids in adults (use a combination
inhaler; avoid separate ICS and LABA inhalers)
3. escalate inhaled corticosteroid dose
4. consider L I RA,long-acting anticholinergics, oral corticosteroids, and biologies (e.g. antiIgE agents, including omalizumab, anti-lL5/lL5R agents,such as mepolizumab, and antiIL-4/13 drugs, including dupilumab)
Emergency Management of Asthma
•see Emergency Medicine, ER29
1.inhaled (52-agonist first line (MD1 route and spacer device recommended)
2.systemic steroids (PO or IV if severe)
3.if severe, add anticholinergic therapy ± magnesium sulfate
4.SC/I V adrenaline if caused by anaphylaxis or if unresponsive to inhaled (52-agonist
5.rapid sequence intubation in life-threatening cases (plus 100% 02, monitors, IV access)
6.inhaled corticosteroid maintenance therapy at discharge
Asthma Action Plan
A written plan developed by providers
for patients with asthma, which includes
signs and symptoms for patients to
recognize acute loss of asthma control
(typically denoted as 'greerf for good
control,‘yellow' for transient loss of
control,or‘
red'
emergency1
zones) and
personalized treatment instructions for
each zone (usually quadrupling inhaled
corticosteroid dose in the yellow zone
for 7-14 days)
Addition of Long-Acting g2-Agonists to
Inhaled Corticosteroids vs.Same Dose Inhaled
Corticosteroidsfor ChronicAsthma in Adults
and Children
Cochiane 08 Syst In2O10:CDOOS53S
Purpose In quantify the solely and effiucyof
addiiion of LABAs to ICS in asthmatic patients
insufficiently controlled on ICS alone.
Methods: RCIs co— paring addition of inhaled LABAs
vs. placebo to the same dose of ICS in children 2 yr
and above and in adults neie included.
Results: II studies.16623 adults and 4626 d ildren.
Addiiion of a daily LABAio ICS reduced risk of
exacerbations requiring oralsteroids by 23% and
led tn a significantly greater improvement in FEV1
compared to ICS monotherapy.
Conclusions: In adults who are symptomatic on low
to high doses ol ICS monotherapy, the addition ol a
LA8A induces rale ol eiaterhaltonsand improves lung
function. In children,the effects of (his treatment
are uncertain.
Guidelines for Asthma Management
Regularly Reassess
• Control
• Risk exacerbation
• Spirometry or PEF
•Inhaler technique
• Adherence
• Triggers
• Comorbidities
• Sputum eosinophils'
rSe'
vetYAsiVmY'
17 yr Add ITPLA
ntli’or tiotropium
6-11 yr: Add LABAorURA
£l2 yrAdd LABA*
6-11 yr I $
II S
Inholad Corticosteroid IICS)*
‘Secoad-liiitt Leuko&ieae R*
c«yitor Antagonist (LTRAl Add a LABA to ICS for patients with any
criteria for poorly controlled asthma (see
Table 11)
<
Low
=
250 H
Doia
^
d' 251
Medium
-500M
Goto
/d >
High
500 Mg
Doia
/d> 'TOOiij d 701-400 iifti'
d > Remember to step down therapy to
lowest doses which maintain good
asthma control fbble 11)
SABA or bud/form* as needed
u‘
Environmental Control. Education, and Written Action Plan S
r"
Confirm Diagnosis £
I
<5; Unconl/olM^^
>
5tn utr oiled 0
UFA Boclomothosono or equivalent;
’
Second line.LTRA, Approved for 12 yr and over.
’
Ufing a formulation approvod for use as a rolievor;
'In adults 18 yr and older with moderate to severe asthma
'Bud/form is approved as a reliever for s.12 years of age and should only be used as a reliever in individuals usingit as monotherapy or in
conjunction withbud/form maintenance therapy
,
"For severe asthma refer to CTS 2017 Recognition and Management of Severe Asthma Position Statement
Figure 9. Guidelines for asthma management
Adapted from:Con J Respir Crit Care Sleep Med 2021:5:6.348-301
Chronic Obstructive Pulmonary Disease
Natural Progression of COPD
40s Chronic productive cough,
wheezing occasionally
50s 1st acute chest illness
60s Dyspnea on exertion,increasing
sputum,more frequent
exacerbations
Late Hypoxemia with cyanosis.
Stage polycythemia, hypercapnia
(morning headache),cor
pulmonale,weight loss
•see Eamilv Medicine. EM19
Definition
•progressive and irreversible condition of the lung characterized by chronic obstruction to airflow with
many patients having periodic exacerbations, gas trapping, lung hyperinflation, and at end stages,
weight loss
•spirometry required for diagnosis (post-bronchodilator l
'EVi/EVC <0.70 or lower limit of normal)
(also often “overdiagnosed” due to inaccuracy of a clinical diagnosis)
•2 phenotypes: chronic bronchitis and emphysema (usually coexist to variable degrees)
•gradual decrease in EEVi over time, more rapidly with each acute exacerbation
L J
+
R9 Respirology Toronto Notes 2023
Table 13. Clinical and Pathologic Features of COPD*
Chronic Bronchitis Emphysema
ICS-Formoterol Relieirer vs.ICS and SABA
Relieverin Asthma:a Systematic Review and
Meta-Analysis
ERi Open Research 2020:7
Purpose: Conduct a systematic review and meta -
arsalysls lo evaluate the efficacy of as needed ICSformoterol versus ICS •as needed SA8A in patients
with mild-mo derate asthma.
Methods:RCTs companrg as needed ICS-formoterol
versus ICS * as neededSABA in adults andfor children
with mild-moderate asthma weie included,eidudmg
studies that did not report severe eiaceihahons.
Databases searched were EMBASE. MEDLINE,the
Cochrane Central Regster of ControlledInals,and
ClinicalTrials.gov.The primary study outcome was
timetofirst exacerbation.
Results: Alter applyingeligibility criteria. 4 RCTs
wtie included in the meta-analysis, all comparing
budesomde DPI budesonde * as neededSABA toDPI
budesomde-formoterol.B.desonde- form otero ' as
needed reduced therate ratio and odds of primary
outcome|RR 0.85,95%Cl 0.73 to 1.00; OR 0.86:95=5
aD.73 tot.01|.
Conclusion: [here was a m odest 15% reduction n
the haiaid ratio ol first eiacerbation with hudeson de
formoterol as needed combination versus the ICS *as
needed SABA maintenance regimen.Currentty.theie
remains no agreed standard for a minimal clinically
important difference.Overall,this study is consistent
with the OIKA 2021recommendations preferring
ICS-formoterol as-needed over ICS maintenance
therapy In mad asthma.Note that Canadian
fjidebnesstill recommend ICS * as needed SABAas
first line for patients with suboptimalcontrol,as d
may he superior to budesomde-formoterol as needed
combination for symptom control,and considers
them egual alternatives for those who have good
symptom control hut are otherwise at high nsk for
exacerbations. A decision aidis available toassist
patients/pioviders when selecting between these
options (www.asthmadecisionaid.coml.
Defined Clinically
Productive cough on most days for at least 3 consecutive months in 2
successive years
Obstruction is mostly due to natiowmg of the airway lumen by mucosal Decreased clastic recoil ol lungparenchyma causes decreased
thickening and excess mucus
Airway changes include increased goblet cells,fibrosis of bronchioles, trapping
loss of tethering due to destruction of alveolar walls
Defined Pathologically
Dilation and destruction of air spaces distal to the terminal bronchiole
without obvious fibrosis
expiratory driving pressure,airway collapse (obstruction),and air
2 Types
1.Ccnlrilobular (respiratory bronchioles predominantly affected)
Typical form seen in smokers,primarily affects upper lung rones
2. Panacinar (all parts of acinus)
Accounts for about1% of emphysema cases,typically from
o1-antitrypsin deficiency,primarily affects lower lobes
’Note that the pathological changes of chronic bronchitis and emphysema can exist without obstruction.Only if spirometric obstruction is also
present is it termed COPD
Risk Factors
• smoking is the al risk factor in Western countries
• environmental:exposure to wood smoke or other biomassfuel for cooking (especially in developing
countries), air pollution, occupational exposures
• treatable factors: a1-antitrypsin deficiency, HIV (accelerated COPD progression), concurrent bronchial
hyperactivity (aslhma-COPD overlap - “ACO”)
• demographic factors: age, history of childhood respiratory infections, low socioeconomic status
Signs and Symptoms
Table 14. Clinical Features and Investigations for Emphysema and Chronic Bronchitis
Symptoms Signs Investigations
Chronic productive cough
Purulent sputum
Cyanosis (2°to hypoxemia)
Peripheral edema from RHF (cor
pulmonale)
Crackles,whceies
Prolonged expiration
FiequenRIy obese
Chronic Bronchitis (Blue
Bloater*)
PFT:
FEVi. 4 FEVi/FVC
N TIC. 4 or N DUO
CXR:
AP diameter normal
t broncbovascular markings
Enlarged heart with cor pulmonale
(end-stage)
Emphysema (Pink Puffer*) Dyspnea|
*
exertion)
Minimal cough
Tachypnea
Decreased exercise tolerance
Pink skin
Pursed-lip breathing
Accessory muscle use
Cachectic appearance due
lo calorie consumption from
increased work of breathing
Hyperinflationfbarrel chest
Hyperresonant percussion
Decreased breath sounds
Decreased diaphragmatic
excursion
PFT:
4 fEVl. 4 fEVi/FVC
•IlC (hyperinflation)
t RV (gas trapping)
4 DUO
Complications of COPD
• Chronic hypoxemia
• Polycythemia 2°to hypoxemia
• Pulmonary HTN (torn loss of vascular
bed (emphysema)
• Cor pulmonale
• Pneumothorax duelo rupture of
emphysematous bullae
• Depression
• COPD exacerbations
CXR:
•
AP diameter
flat hemidiaphragm (on lateral
CXR)
4 cardiac silhouette
t retrosternal space
Bullae
4 peripheral vascular markings
'Note that"blue bloater* and "pink puffer* phenotypes are extremes and most COPD patients have elements olboth.They are also outdated terms
ijiely used Inclinical practice.
COx Retainers
On AB6,retainers have chronically
elevated CQlevels,usually with a
near normal pH (due to metabolic
compensation). Maintain Ox saturation
between 88-92% to prevent
exacerbating hypercapnia due to
worsening V/Q mismatch.Haldane
effect, and/or decreased respiratory
drive (in order of physiologic importance)
rt
t
_ J
Remember,the most important
intervention for COPD patients who
smoke is smoking cessation
+
RIO Respirology Toronto Notes 2023
Table 15. Treatment of Stable COPD
Treatment Details
GOLD Classification of the Severity
of COPD
. GOLD1:Mild FEVi >80% of predicted
. GOLD 2:Moderate 50%<FEVi <80%
of predicted
• GOLD 3:Severe 30% sFEVi <50% of
predicted
• GOLD 4:Very Severe FEVi <30% of
predicted
Note:Use COPO Assessment foollor tompetienshe
iisiessinfflt ol symptoms.w«ik conflation between fIV
- and symptoms
Prolong Survival
Smoking Cessation
Vaccination
Home Oxygen
Counselling,nicotine replacement (long *
short-acting],bupropion,varenicline. combinations tbereol
Annual influenza vaccination;pneumococcal vaccination
Prevents cor pulmonale and decreases mortality ilused >15 h/d:indicated if;
|1) PaO;!55 mmHgor
(2) PaOr 56- 59 mmHg withcor pulmonale or polycythemia
Symptomatic Relief (No Mortality Benefit]
Bronchodilators (mainstay of
current drug therapy,used in
combination)
Short-acting bronchodilators: recommended in allpatients for prnrelief of dyspnea
SABAs (e.g. salbulamol.terbulalme):rapid onset
SAMAs (e.g.ipratropium bromide);slightly more effective than SABAs with fewer side effects but
slower onset
Combination therapy SABAfSAMA can be used
long-acting bronchodilators: recommended to reduce dyspnea,improve exercise tolerance,reduce
exacerbations lor patients with moderate to severe COPD
LABAs (e.g.salmeterol.formoterol.indacaterol)
LAMAs (e.g.tiotropium bromide,glycopyrronium bromide):greater effect at reducing exacerbations
compared lo lABAs
LABA/LAMA dual therapy is recommended in patients with persistent dyspnea,exacerbations,exercise
intolerance,and/or persistently poor health status despite the use of LABA or LAMA monotherapy
LABA/LAMA/ICS triple therapy can be used in patients with persislenl dyspnea and/or exaccrbalions
despite the use ol LABA /LAMA dual therapy
Oral therapies
Insufficient or equivocal evidenceto determine whether the addition of oral theophyllines confers
benefit in stable COPD (high-risk toxicity profile;nervous tremor,nausea/vomiting/diarrhea,
tachycardia,arrhythmias,sleep changes)
PDE4 inhibitor:roflumilast (Daxas31recommended for patients with chronic bronchitisat high risk of
AECOPD
ICS monotherapy has been shown to increase the incidence of pneumonia in COPO:ICSshould only be
used as part of a combination inhaler with LA8A or with LABA /LAMA as triple therapy,in patients with a
history ol exaccrbalions.end-stage disease,and/or concomitant asthma
Oral corticosteroids:used to treat acute exacerbations:patients should be warned of side effects
Lung volume reduction surgery (resection ol emphysematous parts of lung,avoided due to higher
mortality if FEV1 <20%).lung transplant
Patient education,vaccination.oxygen if required,eliminate respiratory irnlants/allergens (occupational/
environmental),exercise rehabilitation toimprove physical endurance
Pulmonary rehabilitation:may reduce mortality if offered within 2wk after hospitalization with an
acute exacerbation of COPD;should be offered to any patient with high symptom burden and/or frequent
exacerbations
Systemic Corticosteroids for AcuteExacerbations
ol ChroaicObstructivc Pulmonary Oiscase
Coc -rane DB Syst Rev 2014:9:CD001228
Study:Cochrane systematic review 16 studies.
Population:1/87 patientswith acute COPD
exacerbations.
Intervention Oral or parenteral corticosteroids
vs.placebo.
Outcome:Tieatnent tailure,risk of relapse,time to
neit COPD exacerbation,likelihood oladverse event,
length of hospital stay, and tun;function at endof
treatment.
Results: Systenuc corticosteroids reduced the
risk of treatment failure hy over half compared
with placebo in rune studies|tr912) with median
treatment duration 14 d. odds ratio|0R) 0.48 (95% Cl
0.35 0.62). Theeridenu was graded us high quality
andit would have been necessary to treat nine people
(95%02-14) with systemic corticosteroids to avod
one treatment failure.There was moderate-quality
ev deuce for a lower rate of relapse at1mo for
treatment with systemic corticosteroid in two studies
|n-4IS)(hazard ratio (HR) 0.28:95% Cl 0.63-0.92).
Mortality up to 30 d was not reduced by treatment
with systemic corticosteroid compared with coatrol
in12 studies (n-1319:OR 1.00:95% Cl 0.60-1.66).
FEVi.measured up to 22 hours,showed significant
increase (2 studies;n-649.mean diflerence (MO)
140 ml95% Cl 90 -200):however,this benefit was
notohserved at later timepoints.The likelihood
of adverse events increased with corticosteroid
treatment (OR 2.33;95%Cl1.59-3.43). Theriskof
hyperglycemia was significantly increased (OR 2.29:
95% Cl1.86-4.19).For general inpatient treatment,
duration ol hospitalization wassignificantly shorter
with corticosteroid treatment (MD -1.22 d;95% Cl
-2.26 to -0.18). with no difference in length of slay io
the intensive care unit (ICU) setting. Comparison ol
parenteral vs.oral treatment showed no significant
diflerence inthe primary outcomes of treatment
failure,relapse, mortality ov for any secondary
outcomes.
Conclusion: Ihere is high quality eridence to support
treatment of exacerbations ol COPO with systemic
corticosteroid hy the oral or parenteral route m
reducungtbe likelihood of treatment failureand
relapse at 1no. shortening lengthof stay «ihospital
Inpatients not requiring assisted ventilation in ICU
and proridmg earlier improvement in lung function
and symptoms. There isno eridence of benefit for
parenteral treatment compared with oral treatment
with cprticosteioid on treatment failure,relapse or
mortakty.There Is an Increase in adveise drug effects
with corticosteroids treatment,which is greater
with parenteral administration compared withoral
treatment.
Corticosteroids
Surgical
Other
| Lung Transplantation
| Oxygen +/- NIV
| Oral Therapies
Pulmonary Rehabilitation
Inhaled Long-Acting Therapies CN
8
Sell-Management Education + Smoking Cessation +
Exercise and Active Lifestyle -f Vaccinations -f Short-Acting
Bronchodilator pm
il
1
-cc
Lung Function
Impairment
Symptoms (CAT) >10
©
Mild Severe !
<0
40
f
Dyspnea (mMRC) 1 4
-
•
t t 8
Prevent/Treat AECOPD
/Assess for
Features of Asthma
Early Diagnosis
(Spirometry) +
Prevention
End 1 -nf-Ljfe Care “
r "i
0
L J
Figure 10. Guidelines for COPD management
Adapted from:Canadian Thoracic Society ClinicalPractice Guideline on pharmacotherapy inpatients with COPO - 2019 update of evidence.Can J
Respir Crit Care Sleep Med 2019;3:4.210-232
Acute Exacerbations of COPD +
•definition
• sustained (>48 h) worsening of dyspnea, cough, or sputum production, often leading to an
increased use of rescue medications
• in addition, defined as either purulent or non-purulent (to predict need for antibiotic therapy)
RU Respirology Toronto Notes 2023
•etiology: viral URT1, bacteria, air pollution, (.
'HI , PE, Ml
•management
ABCs, consider NIV early if high CO:and/or reduced pH
02: target 88-92% SaO:for CO’
retainers
bronchodilators by M DI with spacer or nebulizer
SABA t anticholinergic, e.g.salbutamol and ipratropium bromide via nebulizers
systemic corticosteroids: oral prednisone (if absorption issue can use IV methylprednisolone)
antibioticsfor purulent CORD exacerbations
patients with no risk factorsfor resistant organisms: any of doxycycline/macrolide/amoxicillin/
etc.
• patients with risk factors for resistant organisms: amoxicillin/davulanic acid or respiratory
fluoroquinolone
post exacerbation: rehabilitation within 2 wk if possible
•ICU admission
for life-threatening exacerbations
• ventilatory support
. non-lnvasive: NIPPV (BiPAP)
conventional mechanical ventilation
Dual Combination Therapy vs. Long Acting
Bronchodilators Alone for Chronic Obstructive
ftilmonary Disease (COPO):A Systematic Review
and Network Meta-Analysis
Cochrane DB Syst dev 2018:CD01262O
Study: Cochrane systematic renew ol 99 studes
Population: 101311 participants with moderate to
severe COPD.
Intervention: four Afferent groups of inhalers(Le.
UBA/IAMA combination.LABA.’ICS combination.
LAMA and IABA).
Outcomes: COPO tracerbations(moderate to severe
and severel.symptom and quality of life scores,
safety outcomes, and long function.
Result:LABA 'LAMA combination therapy is most
effective in reducing COPD eracerbations,followed
by LAMA III high-risk and low-risk populations.LABAf
LAMA decreases moderate-lo-severe eiaterbat«os
compared to IABAUCS (HR 0 86:95% credible interval
(Ctl|0.76-0.99). LAMA (HR 0.82: 95% Crl 0.28 to 0.99|.
and LABA in high-risk populations (HR 0.20;95% Crl
0.61-0.801.LAMA decreases moderate-to-severe
eracerbations comparedto IAEA in high-risk (HR
0.80:95% Crl 0.21- 0.88) and low -risk populations
(HI 0.82: 95% Cil 0.28- 0.9)]. lABA /lAMA decreases
severe eyucerbationscompaied to LABA 'ICS (HR
0.28:95% Crl 0.64-0.93) and LABA (HR 0.64:95%
Crl 0.51-0.81) In high-risk populations.There wasa
general trend of the combination therapies having
greater improvement m symptom and quality of life
scores compared to monotherapies. IABAUCS was
the lowest ranked for pneumonia seriousadverse
events in high- risk andlow- nsk populations. LABA ICS
increases the odds of pneumonia compared to LAMA/
LABA (OR 1.69;95% Crl L20-2.44), LAMA (OR1.28:
95% Crl 1.33-2.391, LABA (OR1.50:95% Crl 1.12-192).
the mean difference in lung function for IABA.1
LAMA versus IABA m hqb-iisk population eiceeded
the minimal clinically important difference Quean
dfference 0.13 L:95% Crl 0.10-0.15).
Conclusions: LA8AJLAMAcomb net pi therapy is
most effective in reducing COPO evacerhations.LAVAcontaining therapies may be superior to therapies
without UMA ut reducing COPO evacerhations.
Combination therapies may he more effective than
monotherapies for improving symptoms and quality of
life secures. Therapiesflat contain ICS are associated
with an increased risk of pneumonia.The mean
difference in lung function when comparing IABA'
LAMA versus LABA is Significant.
Prognosis in COPD
•prognostic factors
frequency and severity of acute exacerbations is the single best predictor
• lung function tests and modified Medical Research Council (mMRC) dyspnea scale add value
development of hypoxemia, hypercapnia, or cor pulmonale portend a poor prognosis
•5 yr survival
FEV 1 <1 L = 50%
• PEV 1 <0.75 L = 33%
•BODE index for risk of death in COPD
greater score = higher probability the patient will die from COPD;score can also be used to
predict hospitalization
10 point index consisting of four factors:
Body mass index (BM1): <21 (+1 point)
Obstruction (F'EVl):50-6-1% (+1), 36-49% ( +2), <35% (+ 3)
• Dyspnea ( m.Vl RC scale): walks slower than people of same age on level surface,stops occasionally
(-f -1),stops at 100 yards or a few minutes on the level (+2), too breathless to leave house or
breathless when dressing/undressing (+3)
Exercise capacity (6 min walk distance):250-349 m (+1), 150-249 m (+2), <149 m (+3)
Bronchiectasis
Definition
• irreversible dilatation of airways due to inflammatory destruction of airway walls resulting from
persistently impaired mucous clearance and/or infected mucus
• usually affects medium sized airways
• the most common sputum pathogens found in patients with non-cystic fibrosis are H. influenzae, P.
aeruginosa, M.catarrhalis, and nontuberculous mycobacterium
Table 16. Etiology and Pathophysiology of Bronchiectasis Pulmonary Embolism in Patients with
Unexplained Exacerbation of COPD: Prevalence
and Risk Factors
Ann Intern Med 2006:144:390-396
Study: Prospective cohortstudy
Population: 211 current or former smokers with
COPO who were admitted to the hospital forsevere
euterbation of unknown originand did not require
invasive mechanical ventilation.
Measurements: All patents rece red spiral
Cl ongiogiaphy (CIA) and venous compression
utlrasonography of both legs.
Outcomes: PE positive or PE negative.
Result: 25% of patients met diagnostic criteria for PE
(*CIA or » U/S).
Conclusions: Pie valence of PE in patients
hospitalned lorCOPD exacerbation of unknown origin
is 25%. Therefore,ail patents presenting 10 hospital
with COPD exacerbation without obvious cause
require PE workup (leg doppters or CTA -decs bn
of which to use depends on pre-test probability of
the patient).
Obstruction Post-Infectious (results in dilatation Impaired Defenses/Drainage (leads to
of bronchial walls) chronic infections and inflammation)
Tumour
Foreign body
Pneumonia Hypogammaglobulinemia
IB l r
Nontuberculous mycobacterium (NTM)
Measles
Pertussis
Detective leukocyte function
Allergic bronchopulmonary aspergillosis
Ciliary dysfunction (Karlagenei'
ssyndiomc:
bronchiectasis,sinusitis, situs inversus)
Signs and Symptoms
• chronic cough, copious purulent sputum (but 10-20% have dry cough), dyspnea,fatigue, chronic
rhinosinusitis (for CP and primary ciliary dyskinesia), hemoptysis (can be massive), recurrent chest
infections, local crackles (inspiratory and expiratory), rhonchi, wheezes
• may be difficult to differentiate from chronic bronchitis
r n
cJ
Investigations
• PI- Ts: often demonstrate obstructive pattern but may be normal
. CXR
• nonspecific:Increased markings, linear atelectasis, loss of volume in affected areas
specific: “tram tracking"
- parallel narrow lines radiating from hilurn, cystic spaces
• high-resolution thoracicCl (diagnostic, gold standard)
• 87-97% sensitivity, 93-100% specificity
• “signet ring”:dilated bronchi with thickened walls where diameter of bronchus is >1.5x diameter
of accompanying artery
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R12 Respirology Toronto Notes 2023
•sputum cultures(routine t acid-fast bacillus)
•CBC
•Ll-Ts
•immunoglobulin panel (serum Ig levels),a-1 antitrypsin level, immunology panel (ANA, ENAs),
Rheumatoid factor, HIV test
•sweat chloride if cystic fibrosis is suspected ( upper zone predominant, concomitant features)
•nasal nitric oxide and nasal ciliary biopsy if primary ciliary dyskinesia is suspected
Canadian thoracic Society Clinical Practice
Cuidclinei on long-term Non invasive Ventilation
I or the Management olCOPO
Can J Pespv,CntCare.Sleep Med 2021
Purpose:Khilethe role of non-irrvasrve ventilation
(NIV|has been shown to improve outcomes in acute
COPD eiacerhations with hypercapn ;< respiratory
failure, the efficacy pf long-term home NIV for COPD
management is not as well studied.Ihis document
provides ev dence-hased recommendations for
long-term home (IIH) NIV in chronic hypercapnic
COPD patients.
Methods Apanelolnulbdiscipl nary clinical
eiperts developed dnlcal questions using the PICO
framework, performed a systematic review of the
relevant literature.graded relevant evidence,and
made clinical practice recommendaiionsaccordingly.
Conclusions: tong -term NIV mproressurv val and
reduces hospital leadmission m patents with stable
COPD with significant hypercapnic respnatoiy failure.
Ihere Is some evidence supporting the use of highintensity ventilation over low-intensity ventilation,
the task force supportsthe use of long-term NIV in
thisspecific patient population.
Treatment
•vaccination: influenza and pneumococcal vaccinations
•chest physiotherapy, breathing exercises, physical exercise
•antibiotics (oral, IV, inhaled):
inhaled: used chronically to decrease bacterial load, in patients with frequent exacerbations,
especially if Pseudomonas in sputum
oral/lV: routinely used for exacerbations, driven by sputum sensitivity when available; macrolides
may be used for an anti-inflammatory effect chronically to reduce exacerbation frequency in
patients with frequent exacerbations
•mucolytics (hypertonic saline)
•inhaled corticosteroids: only use if the patient has asthma or other co-existing disease as an indication
•oral corticosteroids have no role in chronic care or acute exacerbations
•pulmonary resection:in selected cases with focal bronchiectasis
•transplant:for end stage diffuse causes (e.g. primary ciliary dyskinesia, CP)
Cystic Fibrosis
• see Paediatrics, P92
Different Durations of Corticosteroid Therapy for
Exacerbations of Chronic Obstructive Pulmonary
D isease
Cochrane OB Syst dev 201S:CD006897
Study:Cochrane systematic rev .ew.8studies.
Population:SS2 patients, with severe or very
severe COPO.
Intervention Corticosleioids gwtn at equivalent
daily dotesfor 3-2 d (short duration) vs.10-15 d
(longer-duration).
Outcome:Treatment failure,risk of relapse, time to
neit COPO exacerbation, likelihood of adverse event,
length of hospitalstay, and lung function at end of
treatment.
Results:In four studiesthere was no differenre m
risk of treatment failuie between short-duration and
longer-duration systemic corticosteroid treatment
(n*457; oddsretro (OR) 0.72, 95% confidence interval
(Cl) 0.36-1.4S). No d < Nerente m risk of relapse|e new
event) was observed between short duration and
longer-duration systemic corticosteroid treatment
(n-457; OR 1.04.95% Cl 0.70-1.56).Time to the
next COPD exacerbation did not differ in one large
study that was powered to detect non-inferiority
and comparedS d vs.14 d pisystemc corbcosteroid
treatment [i*
311; hazard ratio 0.95.95% Cl 0.66
1.37).In five studies no difference m the likelihood of
an adverse eventwasfound between short-duration
and longer-duration systemic corbcosteroid
treatment (n*
503;OR 0.89, 95% Cl 0.46-1.69.length
of hospitalstay (u*
421; mean difference (MD) -0.61
d. 95% Cl -1.51- 0.281 and lung function at the end of
treatment[i*l8S; MD FEV1-0.041:95% Cl -0.19-0.10)
did not differ between short-duration and longerduration treatment.
Conclusions 5 d of oral corkost«o;ds is likely
to he sufheientfor treatment of adults with acute
exacerbations of COPO. and thisrenew suggests
that the likelihood is low thatshorter coursesoi
systemic corticosteroids(of around file days) lead
to worseoutcomesthan are seen with longer (10 to
14 d ) courses.
Pathophysiology
• chloride transport dysfunction: thick secretions from exocrine glands (lung, pancreas, reproductive
tract), and blockage ofsecretory ducts
Clinical Features
• multisystem clinical characteristics:
sinusitis, chronic pulmonary disease
pancreatic insufficiency,meconium ileus in children, distal ileal obstruction, liver disease,
malnutrition
• salt losssyndrome, azoospermia, CP-related DM, bone disease
• chronic lung infections
S. aureus and H . influenzae-, early
• P. aeruginosa: most common in adulthood
• B. cepacia complex:worse prognosis (some subtypes) so infection control is key
• in adults, colonization with more resistant bacteria increases (e.g. PsA, Hurklwhicria cepacia
complex, Stcnotrophomonas, Acliroinobacter, MRSA, NTM etc.)
Investigations
• genetic testing
• autosomal recessive- more than 2100 mutations in CPTR described, not all are disease causing
• sweat chloride test
• increased concentrations of NaCl and K +([Cl—) >60 mmol/Lon two occasions supports the
diagnosis)
• single mutation carriers have normal sweat tests (and no disease)
. PI is
early:airflow limitation in small airways
late:severe airflow obstruction, hyperinflation,gastrapping
. ABGs
• hypoxemia, hypercapnia later in disease with eventual respiratory failure, and cor pulmonale
• CXR
hyperinflation, increased pulmonary markings (especially upper lobes)
Treatment
• chest physiotherapy
• pancreatic enzyme replacements, high fat, high calorie diet
• bronchodilators (salbutamol ± ipratropium bromide)
• inhaled mucolytic (reduces mucus viscosity):hypertonic saline, DNase
• inhaled antibiotics (tobramycin, colistin, aztreonam, levofloxacin, vancomycin )
• anti-inflammatory medications (e.g. azithromycin, ICS if concurrent asthma)
• antibiotics oral and IV (targeted to sputum growth if available, e.g. ciprofloxacin for Pseudomonas, if
sensitive)
• CETR potentiators and modulators (e.g. lvacaftor, Orkambi1
,Svmdeko*)
• lung transplant
r i
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R13Respirology Toronto Notes 2023
Prognosis
• worse prognosis associated with:frequent pulmonary exacerbations, rapid rate of decline of 1-liV1,
supplemental oxygen requirement with exercise orsleep, worsening malnutrition, infection with
difficult to manage organism,Cl-
'
-related DM, pneumothorax, massive hemoptysis
• female gender and low socioeconomic class have greater risk of early death
Usually presents in childhood as
recurrent lung infections that become
persistent and chronic
Interstitial Lung Disease
Correctors (Spedfic Therapies For Class IICFTR
Mutations) for Cystic Fibrosis
Cochrane Database Syst.Iter. 201S;8:C0010966
Purpose: loera-'catethe effects of cyst*
fibrosis
transmembra-ie receptor|CFTR) correctors on
clinically impodantoutcomes,both benefits and
harms,in chi then and adults with CF and classII CFTR
mutations (most commonly F508de:).
Methods:RCTscomparing CF1R correctors to placebo
m people withCF class IImulalions weresearched
in the Cochrane Cystic fibrosis and Genet c Disorders
Cystic Fibrus s Register.Two authors independently
eitracted data and assessed risk of biasand quality
of evidence usi-gGRADE criteria.
Results:Iheq.e '
ity ol ife stores (respiratory
domain) favouredcombination therapy(both
luinacallor-lvacaftor and teiacaltor ivacaltoi|
compared to p
’
aceboat all time points.Ihe mean
increase in cystcMrosis questionnaire (CFO) scores
with tw ice-daily teracaflor |100 mg) and nracaftoc
(ISO mg) was appioiimately 5 points|95%CI 3.20 to
2.00: S04 participants:moderate qua sty evidence!.
KVft predicted improved with both combination
therapies compaied to placebo at(mo.by 5.21%
with lumacaftor-rracaftor 0D (95% CI 3.61it to 6.00%;
504 participations:high quality evidence),and try
2.40% nith jrracaftor ivacaftor BID (06% Cl 0.40%
to 4.40%: 204 paitcipants;low-quality evidence!.
Uoie participants receiving the lumacaftoi-ivacattor
combination reported early breathlessness (OR 2.05:
99% Cl 1.10 to1.83:239 participants:high qoaiity
evidence).These adverse effects were notreported in
the teiacaftor-nracaftor studies.
Conclusions Overall,the deployment oleomb nation
CF1R torrecloctherapies improve quahty-oMlleand
lung (unction inpatents with class IICF.compaied
to placebo controls.Adverse drug effects ten be
mitigated with theuseof tezacaftor-ivacaftoi. when
clinically indrated.
Definition
• a group of disorders which cause diffuse parenchymal lung disease, with progressive scarring of lung
tissue and impairment in lung function and gas exchange
Pathophysiology
• inflammatory and/or fibrosing process in the alveolar walls > distortion and destruction of normal
alveoli and microvasculature
• typically associated with:
lung restriction (decrease in TLC and VC)
decreased lung compliance (increased or normal TEVt/FVC)
• impaired diffusion (decreased DLCO)
• hypoxemia due to V/Q mismatch (usually without hypercapnia until end stage)
• pulmonary HT'N and cor pulmonale occur with advanced disease secondary to hypoxemia and
blood vessel destruction
Etiology
• IPI-*
is the most common cause; however, there are numerous other causes including medication and
radiation related disease
• a careful review of risk factors (e.g. organic/inorganic exposures, connective tissue disease symptoms,
occupational history, medications) is needed during patient evaluation
Table 17. Interstitial Lung Diseases
Unknown Known Etiology
Etiology
Idiopathic
Interstitial
Pneumonias
ILD Associated
with Connective
Tissue Disorders
ILD Associated
with Drugs or
Treatments
Inherited
Disorders
Granulomatous
Disease
Other
IFF (idiopathic Scleroderma Familial IPF
pulmonary fibiosis)
MSIP (non-specific
Interstitial
pneumonia)
H8 IIO (respiraloiy
bronchiolitis eclated
HP (usually oiganic
antigen)
Rheumatoid arthritis Anti-Inflammatory Telomerase mutations Saicoidosis
agents (methotreiate)
Antibiotics
(nitrofurantoin)
langcihans-cell
histiocytosis
LAM [lymphangioleiomyomatosis)
Cianulomalous
lymphocytic ILD
Systemic lupus Caidiovasculat drugs Neurofibromatosis
erythematosus (Sit) (amiodarone)
Chronic eosinophilic
pneumonia
ILD)
DIP (desquamative
Interstitial
pneumonia)
Polymyositis/
deimatomyosilis
Antineoplastic agents Tuberous sclerosis
(chemotherapy
agents)
Pneumoconioses
(inorganic dust):
Silicosis
Asbestosis.
Coal workers
pneumoconiosis,
Chronic beryllium
disease
In ILD think
FASSTEN and BAD RASH
Upper Lung Disease (FASSTEN)
Farmer's lung (HP)
Ankylosing spondylitis
Sarcoidosis
Silicosis
TB COP (cryptogenic
oiganicing
pneumonia)
AIP (acute interstitial
pneumonia)
UP(lymphocytic
organizing
pneumonia)
IPPFE (idiopathic
pleuroparenchymal
fibroelastosis)
ATOP (acute hbiinous
and organizing
pneumonia)
Recreational drugs Gaucher's disease
(e.g. crack lung, talc
granulomatosis)
Radiation
Anti-synthetase
syndiomes Eosinophilic granuloma (Langerhanscell histiocytosis)
Neurofibromatosis
Mized connective
tissue disease
ANCA associated
vasculitis
Lower Lung Disease (BADRASH)
Bronchiolitis obliterans withorganizing
pneumonia (BOOP)fCryptogenlc
Organizing Pneumonia (COP)
Asbestosis
Drugs (nitrofurantoin, hydralazine.INH,
amiodarone. manychemo drugs)
Rhcumatologic disease
Aspiration
Scleroderma
Hamman Rich (acute interstitial
pneumonia) and IPF
Siogren’ssyndrome
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R14 Respirologv Toronto Notes 2023
Signs and Symptoms
• dyspnea, especially on exertion
• nonproductive cough
• crackles (dry, fine, end-inspiratory)
• clubbing (especially in IFF and asbestosis)
• features of cor pulmonale
• note that signs and symptoms vary with underlying disease process
e.g.sarcoidosis isseldom associated with crackles and clubbing
Investigations
• CXR (see Medical Imaging. MM)
• usually decreased lung volumes
• reticular, nodular,or reticulonodular pattern (nodular <3 mm)
hilar/mediastinal adenopathy (bilateral especially in sarcoidosis)
honeycombing
• CT (see Medical Imaging. M161
• four categories when interpretingCT imaging for idiopathic1LD
UIP -reticulation,subpleural and basal predominant, honeycombing ± traction bronchiectasis
• probable UIP -reticulation,subpleural and basal predominant, traction bronchiectasis
indeterminate for UIP - subtle reticulation,subpleural and basal predominant (“early UIP"),CT
features that do notsuggest any specific etiology
alternative diagnosis to IFF- CT features of cysts, mosaic attenuation, predominant ground-glass
opacity, profuse micronodules, centrilohular nodules, consolidation, mid or upper lung zone
predominance, peribronchovascular distribution
The CXR can be normal in up to10% of
patients with interstitial lung disease
• PF'
Fs
restrictive pattern: decreased lung volumes and compliance
normal or increased FEV1/FVC, e.g. flow rates are often normal or high when corrected for
absolute lung volume
- DLCO decreased
• ABGs
hypoxemia and respiratory alkalosis may be present with progression of disease
• other
ANA, RF, anti-CCP, ANCA,and myositis antibodies are performed on a case-by-case basis,
serum-precipitating antibodies to inhaled organic antigens(HP)
bronchoscopy with lavage in select cases
• surgical lung biopsy is considered in patients with CT imaging showing an indeterminate for UIP
and alternative diagnosis to1PF pattern
Unknown Etiologic Agents
IDIOPATHIC PULMONARY FIBROSIS
Definition
• pulmonary fibrosis of unknown cause with UIP histology (found on biopsy or inferred from CT)
• a progressive,irreversible condition
• DDx: connective tissue disease associated-ILD, chronic HP, asbestosis, NSIP
Signs and Symptoms
• commonly presents over age 50,incidence rises with age; males > females
• dyspnea on exertion, nonproductive cough, late inspiratory fine crackles at lung bases, clubbing
Investigations
• labs (nonspecific, autoimmune serology usually negative)
• CXR: reticular or reticulonodular pattern with lower lung predominance;often see honeycombing in
advanced disease
• high resolution CT:typical pattern is one of UIP; ground glass, consolidation,or nodulesshould not
be prominent in 1PF
• biopsy:only if patient has an indeterminate for UIP or alternative diagnosisto IPF pattern on CT
imaging
Treatment
• acute exacerbation:
prednisone
antibiotics and diuretics are considered on an individualized basis ± mechanical ventilation
n
LJ
• ongoing management:
antifibrotic therapy:pirfenidone or nintedanib
• smoking cessation and pulmonary rehab t O’
PPI if patient has reflux
lung transplantation for advanced disease
• prednisone is not used in chronic disease management as it increases mortality, but can be used
during acute exacerbations
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R15 Rcspirology Toronto Notes 2023
Known Etiologic Agents
HYPERSENSITIVITY PNEUMONITIS
IPF Prevalence
. Age 35-44:2-7 per 100000
• Age >75:175 per 100000
Definition
• HP, also known as extrinsic allergic alveolitis,is a spectrum of immune-mediated lung disorders
occurring in response to an inhaled organic antigen
Pathogenesis
• two hit hypothesis:genetic susceptibility/environmental factors plus antigen exposure
• subacute and acute HP are mediated through immune complex formation and inflammation
• chronic HP results from type IV hypersensitivity reaction, T-cell mediated granulomatous
inflammatory response
See Undrcurk Ropirology Inals(able lor more
Moronlion on ASCtND. which details the efficacy and
safety ol oral Mcoidooe in patients with idiopathic
pulmonary fthrosts
•
Etiology
caused by sensitization to inhaled agents, usually organic dust 6
• exposure often related to occupation or hobby
farmer’
slung (thermophilic actinomycetes)
bird breeder’
s/bird fancier’s lung (immune response to bird antigen)
humidifier lung (Aureobasidium pullulans)
sauna taker’slung (v spp.)
• metalworking fluid lung
• may have no identified antigen;likely representssomething in the home environment
Most common presentation of
sarcoidosis:asymptomatic CXR finding
Hilar adenopathy refers to enlargement
of mediastinal lymph nodes which is
most often seen by standard CXR as
spherical/ellipsoidal and/or calcified
nodes.If unilateral, think neoplasia, TB,
or sarcoid.If bilateral,think sarcoid or
lymphoma
Signs and Symptoms
• acute presentation:(4-6 h after exposure)
dyspnea, cough, fever, chills, malaise (lasting 18-24 h )
• subacute presentation: more insidious onset than acute presentation
• chronic presentation
insidious onset over years
• dyspnea, cough,malaise, anorexia, weight loss
Corticosteroids
m
lot Pulmonary Sarcoidosis
Cochra ne OBSyst Rev 2005;2:CDOC1114
Study:Cochrane systematic review ol13RCIs.
Population:1066 participants with pulmonary
sarcoidosis
Inlenreutioiis:steroids(oral or inhaled) versus
control
Outcomes:Improved CXR
Results:Oral steroids demonstrated an
improvement in CXR|tR1.46,95%Cl1.01-2.09).
for inhaled corticosteroids,two studiesshowed no
Improvement in bag function ond one study showed
an improvement in diffusing capably. No data on
side effects.
Conclusions Oralsteroids improve CXR findings and
global scoies of CIl.symptoms, and spiiomelry over
3-24 mo hut do not improve long function or modify
disease course.Oralsterods may be o< benefit for
patients with Stage 2 and 3disease.
Investigations
. CXR
acute: diffuse infiltrates, predominantly upperlobe
chronic:predominantly upper lobe reticulonodular pattern
• HI Ts: acute HF is often obstructive,subacute is obstructive/mixed, chronic is progressively restrictive
• in both acute and chronic HP,serum precipitins may be detectable (neither sensitive nor specific)
Histopathology
• acute HF triad: poorly formed granulomas, cellular bronchiolitis, interstitial lymphocytic infiltrate
• subacute/chronic HF: poorly formed granulomas and multi nucleated giant cells are often seen, may be
difficult to distinguish from U1F
Treatment
• early diagnosis:avoidance of further exposure is critical as chronic changes are irreversible
• systemic corticosteroids can relieve symptoms and speed resolution
• steroid-sparingagents (e.g. mycophenolate, azathioprine) are often used in setting of progressive
disease despite steroids or to preventsteroid related side effects
ft
CXR Fibrotic Patterns
. Asbestosis:lower >upper lobes
, Silicosis:upper > lower lobes
, Coal:upper > lower lobes
SARCOIDOSIS
Definition
• idiopathic non-infcctious granulomatous multi
-system disease with lung Involvement in 90%
• characterized pathologically by non-necrotizing granulomas (although occasionally necrosis is
present)
• numerous human leukocyte antigens and other genetic markers have been shown to play a role and
familial sarcoidosis is now recognized
Epidemiology
• typically affects young and middle-aged patients
• higher incidence among people of African descent (in USA) and from northern latitudes (e.g.
Scandinavia, Canada)
n
L J
Signs and Symptoms
• asymptomatic, cough, dyspnea, fever, arthralgia, malaise, erythema nodosum, chest pain
• chest exam often normal
• common cxtrapulnionary manifestations
eye involvement (anterior or posterior uveitis)
skin involvement (skin papules, erythema nodosum, lupus pernio)
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R16 Respirology Toronto Notts 2023
peripheral lymphadenopathy
arthralgia
hepatomegaly ± splenomegaly
less common extra-pulmonary manifestations involve bone, CNS, kidney, cardiac (arrhythmias,
sudden death,CHI-
'
)
•two acute sarcoid syndromes
• Lofgren’
s syndrome: fever, erythema nodosum, bilateral hilar lymphadenopathy, arthralgias
Heerfordt-Waldenstrom syndrome:fever, parotid enlargement, anterior uveitis, facial nerve palsy
Investigations
•CBC (cytopeniasfrom spleen or marrow involvement, lymphopenia common)
•serum electrolytes, creatinine, liver enzymes, calcium (hypercalcemia/hypcrcalciuria due to vitamin
D activation by granulomas)
•hypergammaglobulinemia, occasionally RF positive
•elevated serum ACE (non-specific and non-sensitive) -reflects total body granuloma load
•CXR: predominantly nodular opacities especially in upper lung zones ± hilar adenopathy
•PR'
s: normal, obstructive pattern, restrictive pattern with normal flow rates and decreased DLCO, or
mixed obstructive/restrictive pattern
•ECG:to rule out conduction abnormalities
•slit-lamp eye exam:to rule out uveitis
Diagnosis
•biopsy
transbronchial lung biopsy, transbronchial lymph node aspiration, EBUS guided lymph node
biopsy, or mediastinoscopic lymph node biopsy for granulomas
in -75% of cases, transbronchial biopsy shows granulomas in the parenchyma even if theCXR is
normal
Staging
•radiographic, based on CXR
Stage 0:normal radiograph
« Stage I:bilateral hilar lymphadenopathy ± paratracheal lymphadenopathy
Stage II: bilateral hilar lymphadenopathy with pulmonary infiltration
• Stage 111:pulmonary infiltration alone ( reticulonodular pattern or nodular pattern)
Stage IV: pulmonary fibrosis (loss of volume in upper lobes common, honeycombing uncommon)
Treatment
•observation if asymptomatic (85% of stage I resolve spontaneously within 2 yr, 50% ofstage II resolve
spontaneously within 5 yr)
•treatment for symptoms, declining lung function, hypercalcemia, or involvement of eye, CNS, kidney,
or heart (not for abnormal CXR alone)
•first line treatment is prednisone
•methotrexate or other immunosuppressives can be used as adjuncts ifsteroid response is
unsatisfactory or assteroid-sparing agents in those who do not tolerate steroids
•lung transplant in end-stage disease
Prognosis
•mortality rangesfrom less than 1% to 8% depending on care setting,severity of disease, and patient
demographics (e.g. age, ethnicity, and sex)
Remember to Involve occupational
health and place of work for data
collection and treatment plan.
Also counsel re:work er'sinsurance as
per jurisdiction (e.g.Workers Safety
Insurance Board (WSIB) in Ontario)
PNEUMOCONIOSES
•group of chronic lung diseases caused by exposure to mineral dusts, and organic dusts
•no effective treatment, therefore key is exposure prevention through the reduction of dust and the use
of protective equipment
•recommend smoking cessation,annual influenza and pneumococcal vaccination, pulmonary
rehabilitation,lung transplant for endstage disease
n
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+
R17 Respirology Toronto Notes 2023
Table 18. Pneumoconioses
Diagnosis Etiology Signs 'Symptoms Investigations Complications
Asbestosis Exposure risks:insulation. Insidious onset
Exposure risks:insulation. Dyspnea
shipyard,construction,
brake linings,pipe fitters, productive
plumbers
Slowly progressive diffuse in asbestosis than silicosis
interstitial fibrosis induced or CWP)
by inhaled asbestos fibres
Usually requires >10-20 yr
of exposure
latency period:20-30 yr
CXt Asbestos exposure
increases risk of
bronchogenic CA and
malignant mesothelioma
Risk of lung cancer
Asbestos exposure can dramatically increased for
also cause pleural and smokers
diaphragmatic plaques
(e calcification),pleural
effusion,roundatelectasis
Microscopic examination
reveals ferruginous
bodies: yellow-brown todshaped structures which
represent asbestos fibres
coaled inmacrophages
Lower >upper lobe
Cough:paroxysmal,noo- Eeticulonodular pattern.
may develop IPE-like
Clubbing (muchmorelikely honeycombing
Silicosis Dyspnea,cough.and CXt Mycobacterial infection
(e.g.IB), chronic
necrotuing aspergillosis.
At risk population:
sandblasters,rock miners, wheecing
stone cutters,quarry and
highway workers
Generally requires >20 yr
exposure:may develop
Upper > lower lobe
Early:nodular disease
(simple pneumoconiosis), lung CA.rheumatic
lung function usually
normal
disorders,kidney
disease,chronic airflow
with much shorter but
heavier exposure
Late:nodules coalesce obstruction,and chronic
into masses (progressive bronchitis
massive fibrosis)
Possible hilar lymph node
enlargement (frequently
calcified),especially
'eggshell*
calcification
At risk populabon:coal Simple CWP
workers,graphite workers Ho signsor symptoms.
usually normallung
function
Complicated CWP (also
known as progressive
massive fibrosis)
Dyspnea course:few
patients progress to
complicated CWP
Simple CWP
CXt:multiple nodular
COPD.chrcrnic renal failure,
rheumatoid arthritis
Coal Workers'
Pneumoconiosis
(coal is less fibrogemc
than silica)
opacities,mostly upper
lobe
Pathologic hallmark is coal
macule
Complicated CWP
CXt:opacities larger and
coalesce
INTERSTITIAL LUNG DISEASE ASSOCIATED WITH DRUGS OR TREATMENTS
Drug-Induced
• antineoplastic agents:bleomycin, mitomycin, busulfan,cyclophosphamide,methotrexate,
chlorambucil, BCNU (carmustine)
• antibiotics: nitrofurantoin, penicillin,sulfonamide
• cardiovascular drugs:amiodarone, tocainide
• anti-inflammatory agents:methotrexate, penicillamine, etanercept, gold salts
• recreational drugs(e.g.heroin, methadone)
• biologies: rituximab, anti-TNF-a agents (infliximab,etanercept,adalimumab), immunotherapy drugs
Radiation-Induced
• acute pneumonitis: typically 4-12 wk post-exposure
• late fibrosis:6-12 mo post-exposure
• infiltrates conform to the shape of the radiation field
r *i
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+
R18 Rcspirology Toronto Notes 2023
Pulmonary Vascular Disease
Pulmonary Hypertension
Definition
• mean pulmonary arterial pressure >20 mmHg with a pulmonary arterial wedge pressure ( PAWP)
£15 mmHg and peripheral vascular resistance (PVR) 3 Wood units measured by right heart
catheterization in supine position at rest
• pulmonary HTN is grouped into 5 categories and classified based on etiology
Table 19. World Health Organization Classification of Pulmonary Hypertension and their
Treatment Options
Consider inAll Patients
withPH
Classification Some Causes Treatment Options
I.Pulmonary Arterial Idiopathic
HIM (PAH)
CCDs lor patients witli
vasoreactivity. Advanced therapy
with single or combination
prostanoids,endolhelin receptor
antagonists (ERA).PDE5
inhibitors.Lung transplantation
for retractor y advanced patients.
Ireatmentolunderlying condition
if relevant
Hereditary mutations
Collagen vascular disease (scleroderma.
SIC.»A|
Congenital heart disease (Eisenmenger
syndrome)
Persistent pulmonary hypertension of the
newborn (PPHN)
PortopulmonaryHIH
HIV infection
Drugs and toiins (e.g.anorexigens)
Schistosomiasis
Pulmonary capillary hemangiomatosis
Pulmonary venooedusive disease (PVOD)
Oxygen therapy
Exercise
Consider anticoagulation
Related to heart failure withpreserved
ejection fraction (HFpEE) or heart lailurewith
reduced ejection fraction (HFrEF)
Lett-sided valvular heart disease (e.g.aortic
stenosis,mitral stenosis)
Congenital/acquired left heart inflow/
outflow tract obstruction and congenital
cardiomyopathies
Obstructive lung disease|C0P0)
Restrictive lung disease (e.g.ILD like
idiopathic pulmonary fibrosis)
Mixed rcslrrctive/obstiuctive lung disease
(e.g.lymphangiolciomyomatosis)
Chronic alveolar hypoxia (chronic high
altitude,alveolar hypoventilation disorders,
sleep-disordered breathing,developmental
lung disorders)
Chronic PE.other pulmonary artery
obstruction (e.g.tumours,parasites,
congenital stenosis)
thromboembolic obstruction ol proximal
pulmonary arteries
Hematologic disorders (e.g.sickle cell)
Systemic disorders (e g.sarcoidosis)
Metabolic disorders
Extrinsic compression ol cential pulmonary
veins (tumour,adenopathy,fibrosing
mediastinibs)
Segmental pulmonary hypertension
II.Pulmonary HIM treat underlying heart disease
due to Lett Heart
Disease
Influenza and pneumococcal
vaccines
Counselling on pregnancy risks
Group IPH (PAH) therapies not
applicable in GroupII PH
Diuretic therapy in patients with
signs of right ventricular failure
and fluidretention
III.Pulmonary HfH
due to lungDisease
and/or Hypoxia
Treat underlying lung disease andI
or cause ol chronic hypoxia and
correct with supplemental oxygen
(proven mortality benefit)
Group IPH (PAH) therapies not
applicable in Group IIIPH
IV.Chronic
Thromboembolic
Pulmonary HTH
(CTEPH)
Anticoagulation,pulmonary
thromboendartereclomy.riociguat
V.Pulmonary
HIH with Unclear
Multifactorial
Mechanisms
Treat underlying cause
Adapted:Simortneau G. Montani 0.Celermajer OS.et al.Haemodynamic definitionsand updated clinical classifications of pulmonary hypertension.
Eut Respir J 2019:53:1801913. fable 2
Guidelines for Vasodilator Response in
Pulmonary Arterial HTN
Selected patients with pulmonary
arterial hypertension (PAH) that respond
to vasodilators acutely,have an
improved survival with long-term use of
high dose CCBs
Vasoreactivity testing: short-acting agent
such as IV epoprostenol.IV adenosine,
or inhaled NO
Positive vasodilator response:decrease
in mean pulmonary arterial pressure
(mPAP) >tO mmHg to <40 mm Hg and
stable/increased cardiac output
Positive vasodilator response: should be
considered as candidate for trial of oral
CC8 therapy
Canada
*
Cardovaxulai Society Cjn.nlwr Ihoratk
ScuvtyPwliooSlatmnil on Pulmonary Hyixitnnwc.
Curuffan Journal ol Cardiology 2020:36:977-992
IDIOPATHIC PULMONARY ARTERIAL HYPERTENSION
(PRIMARY PULMONARY HYPERTENSION)
Definition
• pulmonary HTN in the absence of a demonstrable cause (i.e. Group I )
• disease of the pulmonary artery vessel wall characterized by vasoconstriction, vascular proliferation,
and obstructive remodeling leading to increased pulmonary vascular resistance r "t
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Pathology
• histology includes medial arterial hypertrophy, intimal fibrosis, and plexiform arteriopathy
Epidemiology +
• usually older adults between the ages of 50 and 65, female predominance at younger ages
• most cases are sporadic; familial predisposition in <5% of cases,some linked to mutations in BMPK2
R19 Respirology Toronto Notes 2023
Signs and Symptoms
Table 20. Signs and Symptoms of Pulmonary Hypertension Pulmonary arterial pressures are
measured by pulmonary artery catheters
(ie.Swan-Ganz catheter) which are
inserted into a large vein (often internal
jugular). A balloon at the end of the
catheter tip isinflated causing the
catheter to advance through the right
side of the heart and into the pulmonary
artery. This allowsfor the measurement
of right atrial, right ventricular,
pulmonary artery, and pulmonary
capillary wedge pressures as well as
sampling of mixed venous blood. A
thermistor near the end of the catheter
also allows for assessment of cardiac
output by thermodilution
Symptoms Signs
loud,palpable P2
EV heave
Right-sidedS4 (due to EVH)
Systolic murmur (tricuspid regurgitation (IE))
If right ventricular failure:right sidedS3, increased JYP. positive
hepatojugutar reflux, peripheral edema.IE
Signs of underlying disease
Oyspnea
Fatigue
Retrosternal chest pain
Syncope
Symptoms of underlying disease
Peripheral Edema
Palpitations
'Physical exam may be unremarkable in early disease
Diagnosis
•exclude:
• left heart disease
• lung disease
chronic thromboembolic disease
diseases in Group V PH
known causes of Group 1 PAH
connective tissue diseases
drugs/toxins
congenital heart disease
HIV
schistosomiasis
liver disease
heritable disease
PVOD/pulmonarv capillary hemangiomatosis (PCH)
Investigations
•CXR: enlarged central pulmonary arteries, cardiac changes due to right ventricular enlargement
(filling of retrosternal air space)
•HCG: RVH /right-sided strain (see Cardiology and Cardiac Surgerv. C7)
•2-D echo doppler assessment of right ventricular systolic pressure
•right heart catheterization: to confirm diagnosis through direct measurement of mean pulmonary
arterial pressure, pulmonary capillary wedge pressure, pulmonary vascular resistance, and cardiac
output
•PI-"
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